Results suggest viral control mechanism involves an interaction between IL28B, HLA-C, and KIRs.

Genotyping chronic HCV type 1 patients for variants in HLA-C and KIR genes as well as IL28B can more accurately predict response to therapy using pegylated interferon-alpha and ribavirin than IL28B genotyping alone, researchers claim.

The International Hepatitis C Genetics Consortium (IHCGC) genotyped over 1,000 chronic hepatitis C (CHC) patients of European descent, to evaluate whether they were HLA-C C1 or C2 carriers and for the presence of inhibitory and activating KIR genes, as well as the two IL28B SNPs rs8099917 and rs12979860. Patients were categorized in terms of whether they achieved treatment-induced viral clearance, treatment failure, or demonstrated spontaneous clearance.

Reporting in PLoS Medicine, David R. Booth, M.D. at the University of Sydney’s Westmead Millennium Institute, and colleagues, say their results suggest that evaluating HLA-C genotype as well as IL28B improved the ability to predict treatment failure from 66% to 88%. The findings are detailed in a paper titled “IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study.”

The antiviral activity of natural killer (NK) cells is regulated at least in part through inhibitory and activating killer-cell immunoglobulin-like receptors (KIR) that interact with human leukocyte antigen C (HLA-C) ligands, the authors report. HLA-C group 1 (HLAC1) alleles are ligands for the inhibitory receptors KIR2DL2 and KIR2DL3, and the activating receptor KIR2DS2. HLA-C group 2 (HLA-C2) alleles, on the other hand, are recognized by inhibitory KIR2DL1 and activating KIR2DS1 receptors.

The fact that HLA-C and KIR genes are highly polymorphic means that individuals may carry a diverse range of HLA-C/KIR combinations, and this variation in KIR and HLA expression has been linked with clinical outcomes in a range of diseases including hepatitis C.

To investigate whether the presence of specific HLA-C and KIR variations could help improve the predictive power of IL28B genotyping in terms of therapeutic response in HCV patients, the researchers carried out a  genotyping study in their cohort of 1,000 HCV patients.

IHCGH studies in the same cohort of patients had already shown that the IL28B rs8099917 G allele predicted failure to clear HCV on PegIFN/R therapy. Results from the new study indicated that both homozygous and heterozygous carriers of the G allele were far less likely to achieve a spontaneous clearance, and those who failed to clear the virus after therapy or without therapy were much less likely to have the rs8099917 TT genotype.

The genotyping data further showed that the HLA-C1 and C2 variants were also associated with a number of aspects of viral clearance. In particular, HLA-C2 homozygotes were more likely to fail to clear virus on therapy than other genotypes. Moreover, the HLA-C effect on viral clearance appeared to be a recessive trait, as C1 heterozygotes were no more susceptible to treatment failure than C1 homozygotes, while HLA-C2 homozygosity was no different between those participants with spontaneous virus clearance and healthy controls. “This important observation suggests that the difference in association of HLA-C genotype with viral clearance is due to response to therapy alone, not to the immune response in the absence of therapy,” the team stresses. 

They then tested whether KIR2DL2 or 2DL3 affected response to therapy, protection against development of CHC, or clearance of virus with or without PegIFN/R. The findings concurred with those of previous research, and showed “no effect of KIR genotype per se on viral clearance in any comparison.” However, there was evidence that patients who were KIR2DL3/C2C2 were more likely to fail to clear virus after therapy; this genotype was also more common in patients who failed to clear virus on therapy, in comparison with the combined cohort of patients who achieved viral clearance either with or without treatment.

Evaluation of HLA-C alleles in combination with KIR2DL3 and 2DL2 genes showed evidence of an association with complementary pairs, the team adds, such that the combination of a C1 variant with its inhibiting genes was associated with increased likelihood of treatment response.

Prediction of failure to clear HCV in response to treatment in terms of either IL28B or HLA-C genotypes alone is of limited value clinically due to the relatively low positive predictive value (PPV) for treatment failure, the researchers continue. However, when they tested to see whether both genotypes together could improve this power, they found that prediction of treatment failure improved from 66% when assessing just IL28B G status, to 88% when patients were found to be carriers of IL28B G (IL28B G*) and homozygous for HLA-C2. Interestingly, statistical calculations suggested that the prediction of treatment-induced clearance was additive and interactive between IL28B and HLA-C, and there was evidence of additive and interactive effects between KIR2DL3, KIR2DS1, and HLA-C2 homozygocity.

“These data and previous reports point to HLA-C as being the second gene predicting PegIFN/R treatment response in HCV,” the researchers remark. “This genetic evidence supports an underlying physiological mechanism for HCV viral control involving an interaction between IL28B, HLA-C, and KIRs.”

They suggest that the association of HLA-C with treatment-related viral clearance, but not spontaneous clearance, indicates that on therapy, NK killing of hepatocytes is augmented in HLA-C1 carriers. Moreover, they conclude, “The overall differences in frequency of HLA-C2C2/IL28B G* in healthy controls, those participants with spontaneous virus clearance, sustained viral response, and no sustained viral response groups, suggests a role in pathogenesis for this gene combination.”

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